Lowering serum lipids

ABSTRACT

The present invention provides methods for lowering serum lipids in a patient by administering a GLP-1 agonist. The invention is useful for treating diseases that may be alleviated by lowering serum lipid levels, including, e.g., cardiovascular disease and diabetes.

[0001] The present invention relates to a method for lowering serumlipids, e.g. triglycerides and/or cholesterol in a subject comprisingadministering a GLP-1 agonist to said subject.

BACKGROUND

[0002] Lipids (e.g. cholesterol, cholesterol-ester and triglycerides)are transported in plasma in so called lipoproteins. These lipoproteinsconsist of a spherical hydrophobic core of triglycerides and cholesterolesters surrounded by an amphipathic monolayer of phospholipids,cholesterol and apolipoproteins. Lipoproteins are classified accordingto size/density and nature of associated lipoproteins. The principalclasses of lipoproteins are the following: Chylomicrons are largegut-synthesized particles that transport intestinal absorbed lipids tothe liver and adipose tissue. The liver secretes large triglyceride-richparticles known as VLDL (very-low-density lipoproteins. These particlesare modified peripherally, initially to IDL (intermediate-densitylipoprotein) and later to LDL (low-density-lipoprotein). The latter ischolesterol-rich and it may finally be transformed to small, dense LDL.The liver also secretes cholesterol-rich HDL (high-density-lipoprotein)particles. Vast amount of data links abnormalities in plasma lipoproteinto development of atherosclerosis. Clinical manifestations ofatherosclerosis are the ischemic heart diseases (IHD) like stable andunstable angina pectoris, myocardial infarction and cardiacinsufficiency. Other manifestations are cerebrovascular diseases likestroke and cerebral hemorrhage. Still other manifestations areperipheral artery diseases like intermittent claudication, and aneurismsof aorta and other large arteries.

[0003] The discussion on association between lipoproteins anddevelopment of atherosclerosis has for many years focus on theimportance of LDL cholesterol. Elevated LDL cholesterol is now thoughtto be a causal factor in the development of atherosclerosis and itsassociated diseases It has been increasingly accepted, however thatincreased LDL cholesterol may not be the only lipid and lipoprotein thatconstitutes a risk factor for the development of atherosclerosis.Epidemiological studies have highlighted additional risk factors amongthe lipoproteins. Elevated triglycerides (e.g. elevated VLDL) (Hokanson,J E J, Cardiovasc. Risk, 1996; 3:213-219) and low concentration of HDLcholesterol (Uusitupa, MIJ Circulation 1990; 82: 27-36) have beenidentified as important risk factors.

[0004] Furthermore, changes in particle size of lipoproteins—notreflected in quantitative measurements of said particles—may constituterisk factors for atherosclerosis. Increased concentration of “small,dense LDL” particles, even in situations with normal LDL cholesterol,may be a very significant risk factor (Griffin, B A Atherosclerosis1994; 106: 241-353). Clustering of risk factors may be seen in certainsituations, e.g. diabetic patients very often have dyslipidemiacharacterized by elevated triglycerides, low HDL cholesterol, normal LDLcholesterol but increased amounts of small dense, LDL particles. Inother situation, lipoprotein abnormalities may occur as isolated events,e.g. elevated LDL cholesterol or decreased HDL cholesterol.

[0005] Still another lipoprotein that constitutes a risk factor foratherosclerosis is lipoprotein a (Lp(a)). Lipoprotein(a) [Lp(a)]represents an LDL-like particle to which the Lp(a)-specificapolipoprotein(a) is linked via a disulfide bridge. It has gainedconsiderable interest as a genetically determined risk factor foratherosclerotic vascular disease. Several studies have described acorrelation between elevated Lp(a) plasma levels and coronary heartdisease, stroke, and peripheral atherosclerosis (Kronenberg, F Crit.Rev. Clin. Lab. Sci. 1996; 6: 495-543).

[0006] If one concurs with the notion that atherosclerosis andassociated cardiovascular diseases are related to abnormal levels ofplasma lipids and lipoproteins, then lowering them represent a desirabletherapeutic goal. Lowering of LDL cholesterol through treatment withstatins improves on the mortality from cardiovascular diseases (Lancet1994; 344: 1383-1389). Lowering of triglycerides through treatment withfibrates may also lower the incidence of cardiovascular diseases (Frick,M A New Engl. J. Med. 1987; 317:1237-1245).

[0007] Human GLP-1 is a 37 amino acid residue peptide originating frompreproglucagon which is synthesised i.a. in the L-cells in the distalileum, in the pancreas and in the brain (see i.a.Ørskov C. Glucagon-likepeptide-1, a new hormone of the enteroinsular axis. Diabetologia 1992;35:701-711.). Processing of preproglucagon to give GLP-1(7-36)amide,GLP-1(7-37) and GLP-2 occurs mainly in the L-cells. A simple system isused to describe fragments and analogues of this peptide. Thus, forexample, Gly⁸-GLP-1(7-37) designates a fragment of GLP-1 formallyderived from GLP-1 by deleting the amino acid residues Nos. 1 to 6 andsubstituting the naturally occurring amino acid residue in position 8(Ala) by Gly. Similarly, Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-37)designates GLP-1(7-37) wherein the ε-amino group of the Lys residue inposition 34 has been tetradecanoylated.

[0008] One object of the present invention is to provide compositionswhich can effectively be used in the treatment or prophylaxis ofdyslipidaemia, hyperlipoproteinaemia, hypertriglyceridaemia,hyperlipidaemia or hypercholesterolaemia.

[0009] Another object of the present invention is to providecompositions which can effectively be used in the treatment orprophylaxis of arteriosclerosis including atherosclerosis.

[0010] Other objects of the present invention will become apparent uponreading the present description.

DESCRIPTION OF THE INVENTION

[0011] It has been discovered that GLP-1 lowers plasma levels of lipids,such as triglycerides, cholesterol, and non-estified fatty acid (NEFA)lipids, on a long-term basis.

[0012] Accordingly, the present invention relates to a method oflowering total serum lipids, which method comprises administering to asubject an effective amount of a GLP-1 agonist.

[0013] The invention also relates to a use of a GLP-1 agonist for themanufacture of a medicament for lowering total serum lipids.

[0014] In a further aspect the present invention relates to a method fortreating a human having a disease-state which is alleviated by loweringtotal serum lipids, comprising administering to said human an effectiveamount of a GLP-1 agonist.

[0015] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a human havinga disease-state which is alleviated by lowering total serum lipids.

[0016] In a further aspect the invention relates to a method of loweringLDL, which method comprises administering to a subject an effectiveamount of a GLP-1 agonist.

[0017] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering LDL.

[0018] In a further aspect the present invention relates to a method fortreating a human having a disease-state which is alleviated by loweringLDL, comprising administering to said human an effective amount of aGLP-1 agonist.

[0019] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a human havinga disease-state which is alleviated by lowering LDL.

[0020] In a further aspect the present invention relates to a method oflowering small, dense LDL, which method comprises administering to asubject an effective amount of a GLP-1 agonist.

[0021] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering smal, denseLDL.

[0022] In a further aspect the present invention relates to a method fortreating a human having a disease-state which is alleviated by loweringsmal, dense LDL, comprising administering to said human an effectiveamount of a GLP-1 agonist.

[0023] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a human havinga disease-state which is alleviated by lowering smal, dense LDL.

[0024] In a further aspect the invention relates to a method of loweringVLDL, which method comprises administering to a subject an effectiveamount of a GLP-1 agonist.

[0025] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering VLDL. In afurther aspect the present invention relates to a method for treating ahuman having a disease-state which is alleviated by lowering VLDL,comprising administering to said human an effective amount of a GLP-1agonist.

[0026] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a human havinga disease-state which is alleviated by lowering VLDL.

[0027] In a further aspect the invention relates to a method of loweringtriglycerides, which method comprises administering to a subject aneffective amount of a GLP-1 agonist.

[0028] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering triglycerides.

[0029] In a further aspect the present invention relates to a method fortreating a human having a disease-state which is alleviated by loweringtriglycerides, comprising administering to said human an effectiveamount of a GLP-1 agonist.

[0030] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a human havinga disease-state which is alleviated by lowering triglycerides.

[0031] In a further aspect the invention relates to a method of loweringcholesterol, which method comprises administering to a subject aneffective amount of a GLP-1 agonist.

[0032] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering cholesterol.

[0033] In a further aspect the present invention relates to a method fortreating a human having a disease-state which is alleviated by loweringcholesterol, comprising administering to said human an effective amountof a GLP-1 agonist.

[0034] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a human havinga disease-state which is alleviated by lowering cholesterol.

[0035] In a further aspect the invention relates to a method ofincreasing HDL, which method comprises administering to a subject aneffective amount of a GLP-1 agonist.

[0036] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for increasing HDL.

[0037] In a further aspect the present invention relates to a method fortreating a human having a disease-state which is alleviated byincreasing HDL, comprising administering to said human an effectiveamount of a GLP-1 agonist.

[0038] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a human havinga disease-state which is alleviated by increasing HDL.

[0039] In a further aspect the invention relates to a method of loweringthe LDL/HDL ratio, which method comprises administering to a subject aneffective amount of a GLP-1 agonist.

[0040] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering the LDL/HDLratio.

[0041] In a further aspect the invention relates to a method of loweringfatty acids, which method comprises administering to a subject aneffective amount of a GLP-1 agonist.

[0042] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering fatty acids.

[0043] In a further aspect the invention relates to a method of loweringfree fatty acids (FFA), which method comprises administering to asubject an effective amount of a GLP-1 agonist.

[0044] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering FFA.

[0045] In a further aspect the invention relates to a method of loweringnon-estified fatty acid (NEFA), which method comprises administering toa subject an effective amount of a GLP-1 agonist.

[0046] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for lowering NEFA.

[0047] In a further aspect the present invention relates to use of aGLP-1 agonist for the manufacture of a medicament for lowering plasmalevels of Lp(a) in a human.

[0048] In a further aspect the present invention also relates to use ofa GLP-1 agonist for the manufacture of a medicament for inhibitinggeneration of apo(a) in a human.

[0049] In a further aspect the present invention relates to use of aGLP-1 agonist for the manufacture of a medicament for treating adisease-state which is alleviated by reducing plasma levels of Lp(a) ina human or inhibiting generation of apo(a) in a human.

[0050] In a further aspect the present invention relates to use of aGLP-1 agonist for the manufacture of a medicament for treating prematureocclusive arterial disease in a human which is alleviated by reducingplasma levels of Lp(a) in a human or inhibiting generation of apo(a) ina human.

[0051] In another aspect the present invention is directed to a methodof inhibiting generation of apo(a) in vitro or in vivo by administeringa GLP-1 agonist.

[0052] Moreover, the present invention relates to a method of loweringplasma levels of Lp(a) in a human, comprising administering to saidhuman an effective amount of a GLP-1 agonist.

[0053] Furthermore, the present invention relates to a method ofinhibiting generation of apo(a) in a human, comprising administering tosaid human an effective amount of a GLP-1 agonist.

[0054] Furthermore, the present invention relates to a method fortreating a human having a disease-state which is alleviated by loweringplasma levels of Lp(a) or inhibiting generation of apo(a), comprisingadministering to said human an effective amount of a GLP-1 agonist.

[0055] Furthermore, the present invention relates to a method fortreating premature occlusive arterial disease in a human which isalleviated by lowering plasma levels of Lp(a) or inhibiting generationof apo(a), comprising administering to said human an effective amount ofa GLP-1 agonist.

[0056] In a further aspect the invention relates to a method of treatinga disease selected from cerebrovascular diseases, stroke, cerebralhemorrhage, coronary heart disease, coronary artery disease, diabeticvasculopathy, atherosclerosis, peripheral atherosclerosis,arteriosclerosis, ischemic heart disease, stable and unstable anginapectoris, cardiac insufficiency, myocardial infarction, restenosis,peripheral artery disease, intermittent claudication, aneurisms of aortaand other large arteries, or bypass graft stenosis, which methodcomprises administering to a subject an effective amount of a GLP-1agonist. Each of these diseases is considered an individual embodimentof the invention.

[0057] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a diseaseselected from cerebrovascular diseases, stroke, cerebral hemorrhage,coronary heart disease, coronary artery disease, diabetic vasculopathy,atherosclerosis, peripheral atherosclerosis, arteriosclerosis, ischemicheart disease, stable and unstable angina pectoris, cardiacinsufficiency, myocardial infarction, restenosis, peripheral arterydisease, intermittent claudication, aneurisms of aorta and other largearteries, or bypass graft stenosis. Each of these diseases is consideredan individual embodiment of the invention.

[0058] In a further aspect the invention relates to a method of treatingcardiovascular diseases which method comprises administering to asubject an effective amount of a GLP-1 agonist.

[0059] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating cardiovasculardiseases.

[0060] In a further aspect the invention relates to a method of treatinga disease selected from hyperlipoproteinaemia, hypertriglyceridaemia,hyperlipidaemia, or hypercholesterolaemia, which method comprisesadministering to a subject an effective amount of a GLP-1 agonist. Eachof these diseases is considered an individual embodiment of theinvention.

[0061] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating a diseaseselected from hyperlipidaemia, hyperlipoproteinaemia,hypertriglyceridaemia, or hypercholesterolaemia. Each of these diseasesis considered an individual embodiment of the invention.

[0062] In a further aspect the invention relates to a method of treatingdyslipideamia which method comprises administering to a subject aneffective amount of a GLP-1 agonist.

[0063] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating dyslipidemia.

[0064] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating dyslipidemia ina diabetic patient.

[0065] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating dyslipidemia ina patient having type 1 diabetes, also known as IDDM.

[0066] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treating dyslipidemia ina patient having type 2 diabetes, also known as NIDDM.

[0067] In a further aspect the invention relates to a method of treatingarteriosclerosis which method comprises administering to a subject aneffective amount of a GLP-1 agonist.

[0068] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treatingarteriosclerosis.

[0069] In a further aspect the invention relates to a method of treatingatherosclerosis which method comprises administering to a subject aneffective amount of a GLP-1 agonist.

[0070] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for treatingatherosclerosis.

[0071] In a further aspect the invention relates to a method for thetreatment of patients in a need of an anticoagulative treatment, e.g.following a coronary thrombosis or after surgery, which method comprisesadministering to a subject an effective amount of a GLP-1 agonist.

[0072] In a further aspect the invention relates to a use of a GLP-1agonist for the manufacture of a medicament for anticoagulativetreatment, e.g. following a coronary thrombosis or after surgery.

[0073] The subject or patient is preferably a mammal, more preferably ahuman.

[0074] The use according any one of the above uses in a regimen whichadditionally comprises treatment with human growth hormone, a growthhormone releasing agent or a growth factor such as prolactin orplacental lactogen; the use of human growth hormone, a growth hormonereleasing agent or a growth factor such as prolactin or placentallactogen for the manufacture of a medicament for lowering serum lipidsin a subject; the use of human growth hormone, a growth hormonereleasing agent or a growth factor such as prolactin or placentallactogen for the manufacture of a medicament for lowering serum lipidsin a subject.

[0075] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴, Lys²⁶(N^(ε)-(γ-Glu(N⁶⁰-hexadecanoyl)))-GLP-1(7-37), for the manufacture of a medicament fortreating diabetes type 1 in a regimen which additionally comprisestreatment with insulin.

[0076] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating diabetes type 2 in a regimenwhich additionally comprises treatment with insulin.

[0077] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating dyslipidemia in a patienthaving type 2 diabetes, in a regimen which additionally comprisestreatment with insulin.

[0078] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating diabetes type 2 in a regimenwhich additionally comprises treatment with a sulphonylurea, such as anyone of tolbutamide, glibenclamide, glipizide or glicazide.

[0079] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating dyslipidemia in a patienthaving type 2 diabetes, in a regimen which additionally comprisestreatment with a sulphonylurea, such as any one of tolbutamide,glibenclamide, glipizide or glicazide.

[0080] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating diabetes type 2 in a regimenwhich additionally comprises treatment with a biguanide such asmetformin.

[0081] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating dyslipidemia in a patienthaving type 2 diabetes, in a regimen which additionally comprisestreatment with a biguanide such as metformin.

[0082] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating diabetes type 2 in a regimenwhich additionally comprises treatment with such as repaglinide.

[0083] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating dyslipidemia in a patienthaving type 2 diabetes, in a regimen which additionally comprisestreatment with such as repaglinide.

[0084] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating diabetes type 2 in a regimenwhich additionally comprises treatment with a thiazolidinedione such anyone of troglitazone, ciglitazone, pioglitazone, rosiglitazone, or anyone of the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120,WO 00/41121 and WO98145292.

[0085] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating dyslipidemia in a patienthaving type 2 diabetes, in a regimen which additionally comprisestreatment with a thiazolidinedione such any one of troglitazone,ciglitazone, pioglitazone, rosiglitazone, or any one of the compoundsdisclosed in WO 97/41097, WO 97/41119, WO 97141120, WO 00/41121 and WO98/45292.

[0086] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating diabetes type 1 in a regimenwhich additionally comprises treatment with an α-glucosidase inhibitorsuch as any one of miglitol or acarbose.

[0087] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for the manufactureof a medicament for treating diabetes type 2 in a regimen whichadditionally comprises treatment with an α-glucosidase inhibitor such asany one of miglitol or acarbose.

[0088] In a further aspect the invention relates to a use of a GLP-1agonist, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), for themanufacture of a medicament for treating dyslipidemia in a patienthaving type 2 diabetes, in a regimen which additionally comprisestreatment with an α-glucosidase inhibitor such as any one of miglitol oracarbose.

[0089] In still another embodiment of the invention the present GLP-1agonists may be administered in combination with any one of the insulinsensitizers disclosed in U.S. Pat. Nos. 5,885,997, 6,054,453, WO99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193, and WO00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO00/63189. Preferred insulin sensitizers are selected from(-)-2-ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid and5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiadiazolidine-2,4-dione.

[0090] In a further aspect the invention relates to a use of Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N⁶⁰ -hexadecanoyl)))-GLP-1(7-37) for the manufactureof a medicament for treating diabetes type 1 in a regimen whichadditionally comprises treatment with(−)-2-ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid.

[0091] In a further aspect the invention relates to a use of Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37) for the manufactureof a medicament for treating diabetes type 2 in a regimen whichadditionally comprises treatment with(−)-2-ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid.

[0092] In a further aspect the invention relates to a use of Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N-^(α)-hexadecanoyl)))-GLP-1(7-37) for themanufacture of a medicament for treating dyslipidemia in a patienthaving type 2 diabetes, in a regimen which additionally comprisestreatment with(−)-2-ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid.

[0093] In a further aspect the invention relates to a use of Arg³⁴,Lys²⁶(N^(ξ)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37) for the manufactureof a medicament for treating diabetes type 1 in a regimen whichadditionally comprises treatment with5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiadiazolidine-2,4-dione.

[0094] In a further aspect the invention relates to a use of Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37) for the manufactureof a medicament for treating diabetes type 2 in a regimen whichadditionally comprises treatment with5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiadiazolidine-2,4-dione.

[0095] In a further aspect the invention relates to a use of Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37) for the manufactureof a medicament for treating dyslipidemia in a patient having type 2diabetes, in a regimen which additionally comprises treatment with5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiadiazolidine-2,4-dione.

[0096] In yet another embodiment of the invention the present GLP-1agonists, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), may beadministered in combination with nateglinide.

[0097] In still another embodiment of the invention the present GLP-1agonists, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), are administeredin combination with an antihyperlipidemic agent or antilipidemic agenteg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, probucol or dextrothyroxine.

[0098] Furthermore, the present GLP-1 agonists, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), may beadministered in combination with more than one of the above-mentionedcompounds eg in combination with a sulphonylurea and metformin, asulphonylurea and acarbose, repaglinide and metformin, insulin and asulphonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

[0099] Furthermore, the GLP-1 agonists, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), according to theinvention may be administered in combination with one or moreantiobesity agents or appetite regulating agents. Such agents may beselected from the group consisting of CART (cocaine amphetamineregulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4(melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosisfactor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP(corticotropin releasing factor binding protein) antagonists, urocortinagonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists,MCH (melanocyte-concentrating hormone) antagonists, CCK(cholecystokinin) agonists, serotonin re-uptake inhibitors, serotoninand noradrenaline re-uptake inhibitors, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA(dopamine) agonists (bromocriptin, doprexin), lipase/amylase inhibitors,PPAR modulators, RXR modulators or TR β0 agonists. In another embodimentof the invention the antiobesity agent is leptin. In another embodimentof the invention the antiobesity agent is dexamphetamine or amphetamine.In another embodiment of the invention the antiobesity agent isfenfluramine or dexfenfluramine. In still another embodiment of theinvention the antiobesity agent is sibutramine. In a further embodimentof the invention the antiobesity agent is orlistat. In anotherembodiment of the invention the antiobesity agent is mazindol orphentermine.

[0100] Furthermore, the present GLP-1 agonists, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), may beadministered in combination with one or more antihypertensive agents.Examples of antihypertensive agents are β-blockers such as alprenolol,atenolol, timolol, pindolol, propranolol and metoprolol, ACE(angiotensin converting enzyme) inhibitors such as benazepril,captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril,calcium channel blockers such as nifedipine, felodipine, nicardipine,isradipine, nimodipine, diltiazem and verapamil, and α-blockers such asdoxazosin, urapidil, prazosin and terazosin. Further reference can bemade to Remington: The Science and Practice of Pharmacy, 19th Edition,Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0101] It should be understood that any suitable combination of theGLP-1 agonists with one or more of the above-mentioned compounds andoptionally one or more other pharmacologically active substances areconsidered to be within the scope of the present invention.

[0102] The present GLP-1 agonists, preferably Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37), may alsoadvantageously be combined with diet and/or exercise.

[0103] In one embodiment the GLP-1 agonist is GLP-1(7-37) or GLP-1(7-36)amide.

[0104] In a further embodiment of the invention the GLP-1 agonist is aGLP-1 analogue.

[0105] In a further embodiment of the invention the GLP-1 analogue isselected from the Thr⁸, Met⁸, Gly⁸ and Val⁸ analogues of GLP-1(7-37) andGLP-1(7-36) amide, more preferred the Gly⁸ and Val⁸ analogues ofGLP-1(7-37) and GLP-1(7-36) amide, most preferred the Val⁸ analogues ofGLP-1(7-37) and GLP-1(7-36) amide.

[0106] In a further embodiment of the invention the GLP-1 analogue hasthe formula II:   7   8   9   10   11  12  13  14  15  16  17His-Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa-Xaa-18   19  20  21  22  23  24  25  26  27  28 Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Phe-29   30  31  32  33  34  35  36  37  38IIe-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa 39  40  41  42  43  44  45 Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa (II)

[0107] wherein

[0108] Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, lie, Val, Glu, Asp,Met, or Lys,

[0109] Xaa at position 9 is Glu, Asp, or Lys,

[0110] Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, lie, Val, Glu,Asp, or Lys,

[0111] Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, lie, Val, Glu,Asp, or Lys,

[0112] Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, lie, Tyr,Glu, Asp, or Lys,

[0113] Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, lie, Val, Glu,Asp, or Lys,

[0114] Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, lie, Val, Glu,Asp, or Lys,

[0115] Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys,

[0116] Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, lie, Val,Glu, Asp, or Lys,

[0117] Xaa at position 21 is Glu, Asp, or Lys,

[0118] Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, lie, Val, Glu,Asp, or Lys,

[0119] Xaa at position 23 is Gin, Asn, Arg, Glu, Asp, or Lys,

[0120] Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, lie, Val, Arg,Glu, Asp, or Lys,

[0121] Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, lie, Val, Glu,Asp, or Lys,

[0122] Xaa at position 26 is Lys, Arg, Gin, Glu, Asp, or His,

[0123] Xaa at position 27 is Glu, Asp, or Lys,

[0124] Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, lie, Val, Glu,Asp, or Lys,

[0125] Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys,

[0126] Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, lie, Val, Glu,Asp, or Lys,

[0127] Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Leu, lie, Glu,Asp, or Lys,

[0128] Xaa at position 34 is Lys, Arg, Glu, Asp, or His,

[0129] Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, lie, Val, Glu,Asp, or Lys,

[0130] Xaa at position 36 is Arg, Lys, Glu, Asp, or His,

[0131] Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, lie, Val, Glu,Asp, or Lys, or is deleted,

[0132] Xaa at position 38 is Arg, Lys, Glu, Asp, or His, or is deleted,

[0133] Xaa at position 39 is Arg, Lys, Glu, Asp, or His, or is deleted,

[0134] Xaa at position 40 is Asp, Glu, or Lys, or is deleted,

[0135] Xaa at position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or isdeleted,

[0136] Xaa at position 42 is Pro, Lys, Glu, or Asp, or is deleted,

[0137] Xaa at position 43 is Glu, Asp, or Lys, or is deleted,

[0138] Xaa at position 44 is Glu, Asp, or Lys, or is deleted, and

[0139] Xaa at position 45 is Val, Glu, Asp, or Lys, or is deleted, or(a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, orC-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable saltthereof, provided that

[0140] (i) when the amino acid at position 37, 38, 39, 40, 41, 42, 43 or44 is deleted, then each amino acid downstream of the amino acid is alsodeleted.

[0141] In a further embodiment of the GLP-1 analogue of formula II, theamino acids at positions 37-45 are absent.

[0142] In another embodiment of the GLP-1 analogue of formula II, theamino acids at positions 38-45 are absent.

[0143] In another embodiment of the GLP-1 analogue of formula II, theamino acids at positions 39-45 are absent.

[0144] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Ala, Gly, Ser, Thr, Met, or Val.

[0145] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Gly, Thr, Met, or Val.

[0146] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Val.

[0147] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 9 is Glu.

[0148] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 11 is Thr.

[0149] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 14 is Ser.

[0150] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 16 is Val.

[0151] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 17 is Ser.

[0152] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 18 is Ser, Lys, Glu, or Asp.

[0153] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 19 is Tyr, Lys, Glu, or Asp.

[0154] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 20 is Leu, Lys, Glu, or Asp.

[0155] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 21 is Glu, Lys, or Asp.

[0156] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 22 is Gly, Glu, Asp, or Lys.

[0157] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 23 is Gln, Glu, Asp, or Lys.

[0158] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 24 is Ala, Glu, Asp, or Lys.

[0159] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 25 is Ala, Glu, Asp, or Lys.

[0160] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 26 is Lys, Glu, Asp, or Arg.

[0161] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 27 is Glu, Asp, or Lys.

[0162] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 30 is Ala, Glu, Asp, or Lys.

[0163] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 31 is Trp, Glu, Asp, or Lys.

[0164] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 32 is Leu, Glu, Asp, or Lys.

[0165] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 33 is Val, Glu, Asp, or Lys.

[0166] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 34 is Lys, Arg, Glu, or Asp.

[0167] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 35 is Gly, Glu, Asp, or Lys.

[0168] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 36 is Arg, Lys, Glu, or Asp.

[0169] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 37 is Gly, Glu, Asp, or Lys.

[0170] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 38 is Arg, or Lys, or is deleted.

[0171] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 39 is deleted.

[0172] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 40 is deleted.

[0173] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 41 is deleted.

[0174] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 42 is deleted.

[0175] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 43 is deleted.

[0176] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 44 is deleted.

[0177] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 45 is deleted.

[0178] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 26 is Arg, each of Xaa at positions 37-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-36).

[0179] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 26 is Arg, each of Xaa at positions 38-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-37).

[0180] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 26 is Arg, each of Xaa at positions 39-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-38). In anotherembodiment of the GLP-1 analogue of formula II, Xaa at position 34 isArg, each of Xaa at positions 37-45 is deleted, and each of the otherXaa is the amino acid in native GLP-1(7-36).

[0181] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 34 is Arg, each of Xaa at positions 38-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-37).

[0182] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 34 is Arg, each of Xaa at positions 39-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-38).

[0183] In another embodiment of the GLP-1 analogue of formula II, Xaa atpositions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa atpositions 37-45 is deleted, and each of the other Xaa is the amino acidin native GLP-1(7-36).

[0184] In another embodiment of the GLP-1 analogue of formula II, Xaa atpositions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa atpositions 38-45 is deleted, and each of the other Xaa is the amino acidin native GLP-1(7-37).

[0185] In another embodiment of the GLP-1 analogue of formula II, Xaa atpositions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa atpositions 39-45 is deleted, and each of the other Xaa is the amino acidin native GLP-1(7-38).

[0186] In another embodiment of the GLP-1 analogue of formula II, Xaa atpositions 26 and 34 is Arg, Xaa at position 38 is Lys, each of Xaa atpositions 39-45 is deleted, and each of the other Xaa is the amino acidin native GLP-1(7-38).

[0187] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Thr, Ser, Gly, or Val, Xaa at position 37 is Glu, Xaa atposition 36 is Lys, each of Xaa at positions 38-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-37).

[0188] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Thr, Ser, Gly, or Val, Xaa at position 37 is Glu, Xaa atposition 36 is Lys, each of Xaa at positions 39-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-38).

[0189] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Thr, Ser, Gly or Val, Xaa at position 37 is Glu, Xaa atposition 38 is Lys, each of Xaa at positions 39-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-38).

[0190] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg,each of Xaa at positions 37-45 is deleted, and each of the other Xaa isthe amino acid in native GLP-1(7-36).

[0191] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg,each of Xaa at positions 38-45 is deleted, and each of the other Xaa isthe amino acid in native GLP-1(7-37).

[0192] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg,each of Xaa at positions 39-45 is deleted, and each of the other Xaa isthe amino acid in native GLP-1(7-38).

[0193] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Thr, Ser. Gly, or Val, Xaa at position 18, 23 or 27 isLys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions37-45 is deleted, and each of the other Xaa is the amino acid in nativeGLP-1(7-36).

[0194] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Thr, Ser, Gly, or Val, Xaa at position 18, 23 or 27 isLys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions38-45 is deleted, and each of the other Xaa is the amino acid in nativeGLP-1(7-37).

[0195] In another embodiment of the GLP-1 analogue of formula II, Xaa atposition 8 is Thr, Ser, Gly, or Val, Xaa at position 18, 23 or 27 isLys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions39-45 is deleted, and each of the other Xaa is the amino acid in nativeGLP-1(7-38).

[0196] Such GLP-1 analogues includes, but is not limited to,Arg²⁶-GLP-1(7-37); Arg³⁴-GLP-1(7-37); Lys³⁶-GLP-1(7-37);Arg^(26,34)Lys³⁶-GLP-1(7-37); Arg^(26,34)Lys³⁸GLP-1(7-38);Arg^(26,34)Lys³⁹-GLP-1(7-39); Arg^(26,34)Lys⁴⁰-GLP-1(7-40);Arg²⁶Lys³⁶-GLP-1(7-37); Arg³⁴Lys³⁶-GLP-1(7-37); Arg²⁶Lys³⁹-GLP-1(7-39);Arg³⁴Lys⁴⁰-GLP-1(7-40); Arg^(26,34)Lys^(36,39)-GLP-1(7-39);Arg^(26,34)Lys^(36,40)-GLP-1(7-40); Gly⁸Arg26-GLP-1(7-37);Gly⁸Arg³⁴-GLP-1(7-37); Val⁸-GLP-1(7-37); Thr⁸-GLP-1(7-37);Gly⁸-GLP-1(7-37); Met⁸-GLP-1(7-37); Gly⁸Lys³⁶-GLP-1(7-37);Gly⁸Arg^(26,34)Lys³⁶-GLP-1(7-37); Gly⁸Arg^(26,34)Lys³⁹-GLP-1(7-39);Gly⁸Arg^(26,34)Lys⁴⁰-GLP-1(7-40); Gly⁸Arg²⁶Lys³⁶-GLP-1(7-37);Gly⁸Arg³⁴Lys³⁶-GLP-1(7-37); Gly⁸Arg²⁶Lys³⁹-GLP-1(7-39);Gly⁸Arg³⁴Lys⁴⁰-GLP-1(7-40); Gly⁸Arg^(26,34)Lys^(36,39)-GLP-1(7-39);Gly⁸Arg^(26,34)Lys^(36,40)-GLP-1(7-40); Arg^(26,34)Lys³⁸GLP-1(7-38);Arg^(26,34)Lys³⁹GLP-1(7-39); Arg^(26,34)Lys⁴⁰GLP-1(7-40);Arg^(26,34)Lys⁴¹GLP-1(7-41); Arg^(26,34) Lys⁴²GLP-1(7-42);Arg^(26,34)Lys⁴³GLP-1(7-43); Arg^(26,34)Lys⁴⁴GLP-1(7-44);Arg^(26,34)Lys⁴⁵GLP-1(7-45); Arg^(26,34)Lys³⁸GLP-1(1-38);Arg^(26,34)Lys³⁹GLP-1(1-39); Arg^(26,34)Lys⁴⁰GLP-1(1-40);Arg^(26,34)Lys⁴¹GLP-1(1-41); Arg^(26,34)Lys⁴²GLP-1(1-42);Arg^(26,34)Lys⁴³GLP-1(1-43); Arg^(26,34)Lys⁴⁴GLP-1(1-44);Arg^(26,34)Lys⁴⁵GLP-1(1-45); Arg^(26,34)Lys³⁸GLP-1(2-38);Arg^(26,34)Lys³⁹GLP-1(2-39); Arg^(26,34)Lys⁴⁰GLP-1(2-40);Arg^(26,34)Lys⁴¹GLP-1(2-41); Arg^(26,34)Lys⁴²GLP-1(2-42);Arg^(26,34)Lys⁴³GLP-1(2-43); Arg^(26,34)Lys⁴⁴GLP-1(2-44);Arg^(26,34)Lys⁴⁵GLP-1(2-45); Arg^(26,34)Lys³⁸GLP-1(3-38);Arg^(26,34)Lys³⁹GLP-1(3-39); Arg^(26,34)Lys⁴⁰GLP-1(3-40);Arg^(26,34)Lys⁴¹GLP-1(3-41); Arg^(26,34)Lys⁴²GLP-1(3-42);Arg^(26,34)Lys⁴³GLP-1(3-43); Arg^(26,34)Lys⁴⁴GLP-1(3-44);Arg^(26,34)Lys⁴⁵GLP-1(3-45); Arg^(26,34)Lys³⁸GLP-1(4-38);Arg^(26,34)Lys³⁹GLP-1(4-39); Arg^(26,34)Lys⁴⁰GLP-1(4-40);Arg^(26,34)Lys⁴¹GLP-1(4-41); Arg^(26,34)Lys⁴²GLP-1(4-42);Arg^(26,34)Lys⁴³GLP-1(4-43); Arg^(26,34)Lys⁴⁴GLP-1(4-44);Arg^(28,34)Lys⁴⁵GLP-1(4-45); Arg^(26,34)Lys³⁸GLP-1(5-38);Arg^(26,34)Lys³⁹GLP-1(5-39); Arg^(26,34)Lys⁴⁰GLP-1(5-40);Arg^(26,34)Lys⁴¹GLP-1(5-41); Arg^(26,34)Lys⁴²GLP-1(5-42);Arg^(26,34)Lys⁴³GLP-1(5-43); Arg^(26,34)Lys⁴⁴GLP-1(5-44);Arg^(26,34)Lys⁴⁵GLP-1(5-45); Arg^(26,34)Lys³⁸GLP-1(6-38);Arg^(26,34)Lys³⁹GLP-1(6-39); Arg^(26,34)Lys⁴⁰GLP-1(6-40);Arg^(26,34)Lys⁴¹GLP-1(6-41); Arg^(26,34)Lys⁴²GLP-1(6-42);Arg^(26,34)Lys⁴³GLP-1(6-43); Arg^(26,34)Lys⁴⁴GLP-1(6-44);Arg^(26,34)Lys⁴⁵GLP-1(6-45); Arg²⁶Lys³⁸GLP-1(1-38);Arg³⁴Lys³⁸GLP-1(1-38); Arg^(28,34)Lys^(36,38)GLP-1(1-38);Arg²⁶Lys³⁸GLP-1(7-38); Arg³⁴Lys³⁸GLP-1(7-38);Arg^(26,34)Lys^(36,38)GLP-1(7-38); Arg^(26,34)Lys³⁸GLP-1(7-38);Arg²⁶Lys³⁹GLP-1(1-39); Arg³⁴Lys³⁹GLP-1(1-39);Arg^(26,34)Lys^(36,39)GLP-1(1-39); Arg²⁶Lys³⁹GLP-1(7-39);Arg³⁴Lys³⁹GLP-1(7-39) and Arg^(26,34)Lys^(36,39)GLP-1(7-39). Each one ofthese specific GLP-1 analogues constitutes an alternative embodiment ofthe invention.

[0197] In a still further embodiment of the invention the GLP-1 agonistis a GLP-1 derivative.

[0198] In a further embodiment of the invention the GLP-1 derivative hasone or more lipophilic substituents attached to the parent peptide. Thelipophilic substituents make the profile of action of the parent GLP-1peptide more protracted, make the parent GLP-1 peptide moremetabolically and physically stable, and/or increase the watersolubility of the parent GLP-1 peptide The lipophilic substituent ischaracterised by having a solubility in water at 20° C. in the rangefrom about 0.1 mg/100 ml water to about 250 mg/100 ml water, preferablein the range from about 0.3 mg/100 ml water to about 75 mg/100 ml water.For instance, octanoic acid (C8) has a solubility in water at 20° C. of68 mg/100 ml, decanoic acid (C10) has a solubility in water at 20° C. of15 mg/100 ml, and octadecanoic acid (C18) has a solubility in water at20° C. of 0.3 mg/100 ml.

[0199] In a further embodiment of the invention the GLP-1 derivativespreferably have three lipophilic substituents, more preferably twolipophilic substituents, and most preferably one lipophilic substituent.

[0200] Each lipophilic substituent(s) preferably has 4-40 carbon atoms,more preferably 8-30 carbon atoms, even more preferably 8-25 carbonatoms, even more preferably 12-25 carbon atoms, and most preferably14-18 carbon atoms.

[0201] The lipophilic substituent(s) contain a functional group whichcan be attached to one of the following functional groups of an aminoacid of the parent GLP-1 peptide:

[0202] (a) the amino group attached to the alpha-carbon of theN-terminal amino acid,

[0203] (b) the carboxy group attached to the alpha-carbon of theC-terminal amino acid,

[0204] (c) the epsilon-amino group of any Lys residue,

[0205] (d) the carboxy group of the R group of any Asp and Gu residue,

[0206] (e) the hydroxy group of the R group of any Tyr, Ser and Thrresidue,

[0207] (e) the amino group of the R group of any Trp, Asn, Gin, Arg, andHis residue, or

[0208] (g) the thiol group of the R group of any Cys residue.

[0209] In an embodiment, a lipophilic substituent is attached to thecarboxy group of the R group of any Asp and Glu residue.

[0210] In another embodiment, a lipophilic substituent is attached tothe carboxy group attached to the alpha-carbon of the C-terminal aminoacid.

[0211] In a most preferred embodiment, a lipophilic substituent isattached to the epsilon-amino group of any Lys residue.

[0212] Each lipophilic substituent contains a functional group which maybe attached to a functional group of an amino acid of the parent GLP-1peptide. For example, a lipophilic substituent may contain a carboxylgroup which can be attached to an amino group of the parent GLP-1peptide by means of an amide bond.

[0213] In an embodiment, the lipophilic substituent comprises apartially or completely hydrogenated cyclopentanophenathrene skeleton.

[0214] In another embodiment, the lipophilic substituent is astraight-chain or branched alkyl group.

[0215] In another embodiment, the lipophilic substituent is an acylgroup of a straight-chain or branched fatty acid. Preferably, thelipophilic substituent is an acyl group having the formulaCH₃(CH₂)_(n)CO—, wherein n is an integer from 4 to 38, preferably aninteger from 12 to 38, and most preferably is CH₃(CH₂)₁₂CO—,CH₃(CH₂)₁₄CO—, CH₃(CH₂)₁₆CO—, CH₃(CH₂)₁₈CO—, CH₃(CH₂)₂₀CO— andCH₃(CH₂)₂₂CO—. In a more preferred embodiment, the lipophilicsubstituent is tetradecanoyl. In a most preferred embodiment, thelipophilic substituent is hexadecanoyl.

[0216] In another embodiment of the present invention, the lipophilicsubstituent has a group which is negatively charged such as a carboxylicacid group. For example, the lipophilic substituent may be an acyl groupof a straight-chain or branched alkane α, ω-dicarboxylic acid of theformula HOOC(CH₂)_(m)CO—, wherein m is an integer from 4 to 38,preferably an integer from 12 to 38, and most preferably isHOOC(CH₂)₁₄CO—, HOOC(CH₂)₁₆CO—, HOOC(CH₂)₁₈CO—, HOOC(CH₂)₂₀CO— orHOOC(CH₂)₂₂CO—.

[0217] In a preferred embodiment of the invention, the lipophilicsubstituent is attached to the parent GLP-1 peptide by means of aspacer. A spacer must contain at least two functional groups, one toattach to a functional group of the lipophilic substituent and the otherto a functional group of the parent GLP-1 peptide.

[0218] In an embodiment, the spacer is an amino acid residue except Cysor Met, or a dipeptide such as Gly-Lys. For purposes of the presentinvention, the phrase “a dipeptide such as Gly-Lys” means anycombination of two amino acids except Cys or Met, preferably a dipeptidewherein the C-terminal amino acid residue is Lys, His or Trp, preferablyLys, and the N-terminal amino acid residue is Ala, Arg, Asp, Asn, Gly,Glu, Gln, lie, Leu, Val, Phe, Pro, Ser, Tyr, Thr, Lys, His and Trp.Preferably, an amino group of the parent peptide forms an amide bondwith a carboxylic group of the amino acid residue or dipeptide spacer,and an amino group of the amino acid residue or dipeptide spacer formsan amide bond with a carboxyl group of the lipophilic substituent.

[0219] Preferred spacers are lysyl, glutamyl, asparagyl, glycyl,beta-alanyl and gamma-aminobutanoyl, each of which constitutes anindividual embodiment. Most preferred spacers are glutamyl andbeta-alanyl. When the spacer is Lys, Glu or Asp, the carboxyl groupthereof may form an amide bond with an amino group of the amino acidresidue, and the amino group thereof may form an amide bond with acarboxyl group of the lipophilic substituent. When Lys is used as thespacer, a further spacer may in some instances be inserted between theε-amino group of Lys and the lipophilic substituent. In one embodiment,such a further spacer is succinic acid which forms an amide bond withthe ε-amino group of Lys and with an amino group present in thelipophilic substituent. In another embodiment such a further spacer isGlu or Asp which forms an amide bond with the ε-amino group of Lys andanother amide bond with a carboxyl group present in the lipophilicsubstituent, that is, the lipophilic substituent is a N^(ε)-acylatedlysine residue.

[0220] In another embodiment, the spacer is an unbranched alkaneα,ω-dicarboxylic acid group having from 1 to 7 methylene groups, whichspacer forms a bridge between an amino group of the parent peptide andan amino group of the lipophilic substituent. Preferably, the spacer issuccinic acid.

[0221] In a further embodiment, the lipophilic substituent with theattached spacer is a group of the formula CH₃(CH₂)_(p)NH—CO(CH₂)_(q)CO—,wherein p is an integer from 8 to 33, preferably from 12 to 28 and q isan integer from 1 to 6, preferably 2.

[0222] In a further embodiment, the lipophilic substituent with theattached spacer is a group of the formulaCH₃(CH₂)_(r)CO—NHCH(COOH)(CH₂)₂CO—, wherein r is an integer from 4 to24, preferably from 10 to 24.

[0223] In a further embodiment, the lipophilic substituent with theattached spacer is a group of the formulaCH₃(CH₂)_(s)CO—NHCH((CH₂)₂COOH)CO—, wherein s is an integer from 4 to24, preferably from 10 to 24.

[0224] In a further embodiment, the lipophilic substituent is a group ofthe formula COOH(CH₂)_(t)CO— wherein t is an integer from 6 to 24.

[0225] In a further embodiment, the lipophilic substituent with theattached spacer is a group of the formula—NHCH(COOH)(CH₂)₄NH—CO(CH₂)_(u)CH₃, wherein u is an integer from 8 to18.

[0226] In a further embodiment, the lipophilic substituent with theattached spacer is a group of the formulaCH₃(CH₂)_(v)CO—NH—(CH₂)_(z)—CO, wherein v is an integer from 4 to 24 andz is an integer from 1 to 6.

[0227] In a further embodiment, the lipophilic substituent with theattached spacer is a group of the formula—NHCH(COOH)(CH₂)₄NH—COCH((CH₂)₂COOH)NH—CO(CH₂)_(w)CH₃, wherein w is aninteger from 10 to 16.

[0228] In a further embodiment, the lipophilic substituent with theattached spacer is a group of the formula—NHCH(COOH)(CH₂)₄NH—CO(CH₂)₂CH(COOH)NHCO(CH₂)_(x)CH₃, wherein x is zeroor an integer from 1 to 22, preferably 10 to 16.

[0229] In a further embodiment the GLP-1 derivative is derived from aGLP-1 fragment selected from the group comprising GLP-1(7-35),GLP-1(7-36), GLP-1(7-36)amide, GLP-1(7-37), GLP-1(7-38), GLP-1(7-39),GLP-1(7-40) and GLP-1(7-41) or an analogue thereof.

[0230] In a further embodiment of the GLP-1 derivative the designationanalogue comprises derivatives wherein a total of up to fifteen,preferably up to ten amino acid residues have been exchanged with anyα-amino acid residue.

[0231] In a further embodiment of the GLP-1 derivative the designationanalogue comprises derivatives wherein a total of up to fifteen,preferably up to ten amino acid residues have been exchanged with anyα-amino acid residue which can be coded for by the genetic code.

[0232] In a further embodiment of the GLP-1 derivative the designationanalogue comprises derivatives wherein a total of up to six amino acidresidues have been exchanged with another α-amino acid residue which canbe coded for by the genetic code.

[0233] In a further embodiment the GLP-1 derivative is a GLP-1derivative of formula I:   7   8   9   10  11  12  13  14  15  16  17His-Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa-Xaa-18   19  20  21  22  23  24  25  26  27  28Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Phe-29   30  31  32  33  34  35  36  37  38Ile-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa 39  40  41  42  43  44  45 Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa (I)

[0234] wherein

[0235] Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp,Met, or Lys,

[0236] Xaa at position 9 is Glu, Asp, or Lys,

[0237] Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu,Asp, or Lys,

[0238] Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu,Asp, or Lys,

[0239] Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr,Glu, Asp, or Lys,

[0240] Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu,Asp, or Lys,

[0241] Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu,Asp, or Lys,

[0242] Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys,

[0243] Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val,Glu, Asp, or Lys,

[0244] Xaa at position 21 is Glu, Asp, or Lys,

[0245] Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu,Asp, or Lys,

[0246] Xaa at position 23 is Gin, Asn, Arg, Glu, Asp, or Lys,

[0247] Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg,Glu, Asp, or Lys,

[0248] Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu,Asp, or Lys,

[0249] Xaa at position 26 is Lys, Arg, Gin, Glu, Asp, or His,

[0250] Xaa at position 27 is Glu, Asp, or Lys,

[0251] Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu,Asp, or Lys,

[0252] Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys,

[0253] Xaa at position 32 is Leu, Gly, Sa, Ser, Thr, Ile, Val, Glu, Asp,or Lys,

[0254] Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Leu, Ile, Glu,Asp, or Lys,

[0255] Xaa at position 34 is Lys, Arg, Glu, Asp, or His,

[0256] Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu,Asp, or Lys,

[0257] Xaa at position 36 is Arg, Lys, Glu, Asp, or His,

[0258] Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu,Asp, or Lys, or is deleted,

[0259] Xaa at position 38 is Arg, Lys, ,Glu, Asp, or His, or is deleted,

[0260] Xaa at position 39 is Arg, Lys, Glu, Asp, or His, or is deleted,

[0261] Xaa at position 40 is Asp, Glu, or Lys, or is deleted,

[0262] Xaa at position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or isdeleted,

[0263] Xaa at position 42 is Pro, Lys, Glu, or Asp, or is deleted,

[0264] Xaa at position 43 is Glu, Asp, or Lys, or is deleted,

[0265] Xaa at position 44 is Glu, Asp, or Lys, or is deleted, and

[0266] Xaa at position 45 is Val, Glu, Asp, or Lys, or is deleted, or(a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, orC-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable saltthereof, provided that

[0267] (i) when the amino acid at position 37, 38, 39, 40, 41, 42, 43 or44 is deleted, then each amino acid downstream of the amino acid is alsodeleted,

[0268] (ii) the derivative of the GLP-1 analog contains only one or twoLys,

[0269] (iii) the ε-amino group of one or both Lys is substituted with alipophilic substituent optionally via a spacer.

[0270] In a further embodiment of the GLP-1 derivative of formula I, theamino acids at positions 37-45 are absent.

[0271] In another embodiment of the GLP-1 derivative of formula I, theamino acids at positions 38-45 are absent.

[0272] In another embodiment of the GLP-1 derivative of formula I, theamino acids at positions 39-45 are absent.

[0273] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 8 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or, Lys,In another embodiment of the GLP-1 derivative of formula I, Xaa atposition 8 is Ala, Gly, Ser, Thr, or Val.

[0274] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 9 is Glu.

[0275] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 11 is Thr.

[0276] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 14 is Ser.

[0277] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 16 is Val.

[0278] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 17 is Ser.

[0279] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 18 is Ser, Lys, Glu, or Asp.

[0280] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 19 is Tyr, Lys, Glu, or Asp.

[0281] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 20 is Leu, Lys, Glu, or Asp.

[0282] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 21 is Glu, Lys, or Asp.

[0283] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 22 is Gly, Glu, Asp, or Lys.

[0284] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 23 is Gin, Glu, Asp, or Lys.

[0285] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 24 is Ala, Glu, Asp, or Lys.

[0286] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 25 is Ala, Glu, Asp, or Lys.

[0287] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 26 is Lys, Glu, Asp, or Arg.

[0288] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 27 is Glu, Asp, or Lys.

[0289] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 30 is Ala, Glu, Asp, or Lys.

[0290] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 31 is Trp, Glu, Asp, or Lys.

[0291] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 32 is Leu, Glu, Asp, or Lys.

[0292] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 33 is Val, Glu, Asp, or Lys.

[0293] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 34 is Lys, Arg, Glu, or Asp.

[0294] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 35 is Gly, Glu, Asp, or Lys.

[0295] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 36 is Arg, Lys, Glu, or Asp.

[0296] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 37 is Gly, Glu, Asp, or Lys.

[0297] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 38 is Arg, or Lys, or is deleted.

[0298] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 39 is deleted.

[0299] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 40 is deleted.

[0300] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 41 is deleted.

[0301] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 42 is deleted.

[0302] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 43 is deleted.

[0303] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 44 is deleted.

[0304] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 45 is deleted.

[0305] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 26 is Arg, each of Xaa at positions 37-45 is deleted, andeach of the other Xaa is the amino acid in native GLP-1(7-36).

[0306] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 26 is Arg, each of Xaa at positions 38-45 is deleted, andeach of the other Xaa is the amino acid in native GLP-1(7-37).

[0307] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 26 is Arg, each of Xaa at positions 39-45 is deleted, andeach of the other Xaa is the amino acid in native GLP-1(7-38).

[0308] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 34 is Arg, each of Xaa at positions 37-45 is deleted, andeach of the other Xaa is the amino acid in native GLP-1(7-36).

[0309] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 34 is Arg, each of Xaa at positions 38-45 is deleted, andeach of the other Xaa is the amino acid in native GLP-1(7-37).

[0310] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 34 is Arg, each of Xaa at positions 39-45 is deleted, andeach of the other Xaa is the amino acid in native GLP-1(7-38).

[0311] In another embodiment of the GLP-1 derivative of formula I, Xaaat positions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa atpositions 37-45 is deleted, and each of the other Xaa is the amino acidin native GLP-1(7-36).

[0312] In another embodiment of the GLP-1 derivative of formula I, Xaaat positions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa atpositions 38-45 is deleted, and each of the other Xaa is the amino acidin native GLP-1(7-37).

[0313] In another embodiment of the GLP-1 derivative of formula I, Xaaat positions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa atpositions 39-45 is deleted, and each of the other Xaa is the amino acidin native GLP-1(7-38).

[0314] In another embodiment of the GLP-1 derivative of formula I, Xaaat positions 26 and 34 is Arg, Xaa at position 38 is Lys, each of Xaa atpositions 39-45 is deleted, and each of the other Xaa is the amino acidin native GLP-1(7-38).

[0315] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 8 is Thr, Ser, Gly or Val, Xaa at position 37 is Glu, Xaa atposition 36 is Lys, each of Xaa at positions 38-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-37).

[0316] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 8 is Thr, Ser, Gly or Val, Xaa at position 37 is Glu, Xaa atposition 36 is Lys, each of Xaa at positions 39-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-38).

[0317] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 8 is Thr, Ser, Gly or Val, Xaa at position 37 is Glu, Xaa atposition 38 is Lys, each of Xaa at positions 39-45 is deleted, and eachof the other Xaa is the amino acid in native GLP-1(7-38).

[0318] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg,each of Xaa at positions 37-45 is deleted, and each of the other Xaa isthe amino acid in native GLP-1(7-36).

[0319] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg,each of Xaa at positions 38-45 is deleted, and each of the other Xaa isthe amino acid in native GLP-1(7-37).

[0320] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg,each of Xaa at positions 39-45 is deleted, and each of the other Xaa isthe amino acid in native GLP-1(7-38).

[0321] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 8 is Thr, Ser, Gly, or Val, Xaa at position 18, 23 or 27 isLys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions37-45 is deleted, and each of the other Xaa is the amino acid in nativeGLP-1(7-36).

[0322] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 8 is Thr, Ser, Gly, or Val, Xaa at position 18, 23 or 27 isLys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions38-45 is deleted, and each of the other Xaa is the amino acid in nativeGLP-1(7-37).

[0323] In another embodiment of the GLP-1 derivative of formula I, Xaaat position 8 is Thr, Ser, Gly, or Val, Xaa at position 18, 23 or 27 isLys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions39-45 is deleted, and each of the other Xaa is the amino acid in nativeGLP-1(7-38).

[0324] Such GLP-1 derivatives includes, but is not limited to,

[0325] Lys³⁴ (N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-37),

[0326]Arg^(26,34),Lys⁸(N^(ε)-(γ-glutamyl(N^(α)-hexadecanoyl)))-GLP-1(7-37),

[0327] Arg³⁴,Lys²⁶(N^(ε)-(γ-glutamyl(N^(α)-dodecanoyl)))-GLP-1(7-37),

[0328] Arg³⁴,Lys²⁶(N^(ε)-(β-alanyl(N^(α)-hexadecanoyl)))-GLP-1(7-37),

[0329] Arg³⁴,Lys²⁶(N^(ε)-(α-glutamyl(N^(α)-hexadecanoyl)))-GLP-1(7-37),

[0330]Arg³⁴,Lys²⁶(N^(ε)-(piperidinyl-4-carbonyl(N-hexadecanoyl)))-GLP-1(7-37),

[0331] Arg³⁴,Lys²⁶(N^(ε)-(γ-glutamyl(N^(α)-decanoyl)))-GLP-1(7-37),

[0332]Glu^(22,23,30)Arg^(26,34)Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0333]Glu^(23,26)Arg³⁴Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0334]Lys^(26,34)-bis(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-37)-OH,

[0335]Lys^(26,34)-bis(N^(ε)-(γ-glutamyl(N^(α)-hexadecanoyl)))-GLP-1(7-37)-OH,

[0336]Arg³⁴Lys²⁶(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-37)-OH,

[0337]Arg^(26,34)Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-hexadecanoyl)))-GLP-1(7-38)-OH,

[0338]Arg^(26,34)Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-hexadecanoyl)))-GLP-1(7-38)-OH,

[0339]Arg³⁴Lys²⁶(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GKP-1(7-37)-OH,

[0340]Arg^(26,34)Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-octadecanoyl)))-GLP-1(7-38)-OH,

[0341]Glu^(22,23,30)Arg^(26,34)Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0342]Glu^(23,26)Arg³⁴Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0343] Lys^(26,34)-bis(N^(ε)-(ω-carboxylridecanoyl))-GLP-1(7-37)-OH,

[0344]Lys^(26,34)-bis(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoly)))-GLP-1(7-37)-OH,

[0345] Arg^(26,34)Lys³⁸(N^(ε)-(ω-carboxypentadecanoyl))-GLP-1(7-38)-OH,

[0346]Lys^(26,34)-bis(N^(ε)-(γ-glutamyl(N^(α)-hexadecanoyl)))-GLP-1(7-37)-OH,

[0347]Arg³⁴Lys²⁶(N^(ε)-(γ-glutamyl(N^(α)-hexadecanoyl)))-GLP-1(7-37)-OH,

[0348]Arg^(26,34)Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0349] Arg^(26,34)Lys³⁸(N^(ε)-(ω-carboxypentadecanoyl))-GLP-1(7-38)-OH,

[0350]Arg^(26,34)Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-hexadecanoyl)))-GLP-1(7-38)-OH,

[0351] Arg^(18,23,26,30,34)Lys³⁸((N^(ε)-hexadecanoyl)-GLP-1(7-38)-OH,

[0352] Arg^(26,34)Lys³⁸(N^(ε)-(ω-carboxylridecanoyl))-GLP-1(7-38)-OH,

[0353]Arg³⁴Lys²⁶(N^(ε)-(γ-glutamyl(N^(α)-tetradecanoyl)))-GLP-1(7-37)-OH,

[0354]Arg^(26,34)Lys³⁸(N^(ε)-(γ-glutamyl(N^(α)-octadecanoyl)))-GLP-1(7-38)-OH,

[0355]Glu^(22,23,30)Arg^(26,34)Lys³⁸(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0356]Glu^(23,26)Arg³⁴Lys³⁸(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0357]Lys^(26,34)-bis(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP-1(7-37)-OH,

[0358]Lys^(26,34)-bis(N^(ε)-(β-alanyl(N^(α)-hexadecanoyl)))-GLP-1(7-37)-OH,

[0359] Arg³⁴Lys²⁶(N^(ε)-(β-alanyl(N^(α)-hexadecanoyl)))-GLP-1(7-37)-OH,

[0360]Arg^(26,34)Lys³⁸(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0361]Arg^(26,34)Lys³⁸(N^(ε)-(β-alanyl(N^(α)-hexadecanoyl)))-GLP-1(7-38)-OH,

[0362] Arg³⁴Lys²⁶(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP-1(7-37)-OH,

[0363]Arg^(26,34)Lys³⁸(N^(ε)-(β-alanyl(N^(α)-octadecanoyl)))-GLP-1(7-38)-OH.

[0364]Glu^(22,23,30)Arg^(26,34)Lys³⁸(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0365]Glu^(23,26)Arg³⁴Lys³⁸(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP1(7-37)-OH,

[0366]Lys^(26,34)-bis(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP-1(7-37)-OH,

[0367]Lys^(26,34)-bis(N^(ε)-(β-alanyl(N^(α)-hexadecanoyl)))-GLP-1(7-37)-OH,

[0368] Arg³⁴Lys²⁶(N^(ε)-(β-alanyl(N^(α)-hexadecanoyl)))-GLP-1(7-37)-OH,

[0369]Arg^(26,34)Lys³⁸(N^(ε)-(β-alanyl(N^(α)-tetradecanoyl)))-GLP-1(7-38)-OH,

[0370]Arg^(26,34)Lys³⁸(N^(ε)-(β-alanyl(N^(α)-hexadecanoyl)))-GLP-1(7-38)-OH,

[0371] Arg³⁴Lys²⁶(N^(ε)-(βalanyl(N^(α)-tetradecanoyl)))-GLP-1(7-37)-OH,

[0372]Arg^(26,34)Lys³⁸(N^(ε)-(β-alanyl(N^(α)-octadecanoyl)))-GLP-1(7-38)-OH,

[0373] Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0374] Lys³⁴ (N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0375] Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0376] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0377] Gly⁸Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0378] Gly⁸Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0379] Val⁸Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0380] Val⁸Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0381] Val⁸Lys^(26,34) -bis(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0382] Arg²⁶Lys³⁴ (N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0383] Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0384] Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0385] Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0386] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0387] Gly⁸Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0388] Gly⁸Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0389] Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0390] Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0391] Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0392] Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0393] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0394] Gly⁸Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0395] Gly⁸Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0396] Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0397] Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0398] Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0399] Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0400] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0401] Gly⁸Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0402] Gly⁸Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0403] Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0404] Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-36);

[0405] Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-36);

[0406] Lys^(26,34)-bis(^(ε)-tetradecanoyl)-GLP-1(7-36);

[0407] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-36);

[0408] Gly⁸Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-36);

[0409] Gly⁸Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-36);

[0410] Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-36);

[0411] Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-35);

[0412] Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-35);

[0413] Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-35);

[0414] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-35);

[0415] Gly⁸Lys³⁴ (N^(ε)-tetradecanoyl)-GLP-1(7-35);

[0416] Gly⁸Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-35);

[0417] Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-35);

[0418] Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-36)amide;

[0419] Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-36)amide;

[0420] Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-36)amide;

[0421] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)-GLP-1(7-36)amide;

[0422] Gly⁸Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-36)amide;

[0423] Gly⁸Lys^(26,34)-bis(N^(ε)-tetradecanoyl)-GLP-1(7-36)amide;

[0424] Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-36)amide;

[0425] Gly⁸Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0426] Lys²⁶(N^(ε)-tetradecanoyl)Arg³⁴-GLP-1(7-37);

[0427] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)Arg³⁴-GLP-1(7-37);

[0428] Arg^(26,34)Lys³⁶(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0429] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-tetradecanoyl)-GLP-1(7-37);

[0430] Gly⁸Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-35);

[0431] Lys²⁶(N^(ε)-tetradecanoyl)Arg³⁴-GLP-1(7-38);

[0432] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)Arg³⁴-GLP-1(7-38);

[0433] Arg^(26,34)Lys³⁶(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0434] Arg^(26,34)Lys³⁸(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0435] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-tetradecanoyl)-GLP-1(7-38);

[0436] Gly⁸Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0437] Lys²⁶(N^(ε)-tetradecanoyl)Arg-GLP-1(7-39);

[0438] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)Arg³⁴-GLP-1(7-39);

[0439] Arg^(26,34)Lys³⁶(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0440] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-tetradecanoyl)-GLP-1(7-39);

[0441] Gly⁸Arg²⁶Lys³⁴(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0442] Lys²⁶(N^(ε)-tetradecanoyl)Arg³⁴-GLP-1(7-40);

[0443] Gly⁸Lys²⁶(N^(ε)-tetradecanoyl)Arg³⁴-GLP-1(7-40);

[0444] Arg^(26,34)Lys³⁶(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0445] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-tetradecanoyl)-GLP-1(7-40);

[0446] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0447] Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0448] Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0449] Gly⁸Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0450] Gly⁸Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0451] Gly⁸Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0452] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0453] Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0454] Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0455] Gly⁸Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0456] Gly⁸Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0457] Gly⁸Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0458] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-39);

[0459] Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-39);

[0460] Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-39);

[0461] Gly⁸Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-39);

[0462] Gly⁸Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-39);

[0463] Gly⁸Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-39);

[0464] Lys²⁶ (N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0465] Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0466] Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0467] Gly⁸Lys^(26 -bis(N) ^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0468] Gly⁸Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0469] Gly⁸Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0470] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36);

[0471] Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36);

[0472] Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36);

[0473] Gly⁸Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36);

[0474] Gly⁸Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36);

[0475] Gly⁸Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36);

[0476] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36)amide;

[0477] Lys³⁴ (N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36)amide;

[0478] Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36)amide;

[0479] Gly⁸Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36)amide;

[0480] Gly⁸Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36)amide;

[0481] Gly⁸Lys26,34-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-36)amide;

[0482] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-35);

[0483] Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-35);

[0484] Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-35);

[0485] Gly⁸Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-35);

[0486] Gly⁸Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-35);

[0487] Gly⁸Lys^(26,34)-bis(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-35);

[0488] Arg²⁶Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0489] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0490] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))Arg³⁴-GLP-1(7-37);

[0491] Gly⁸Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))Arg³⁴-GLP-1(7-37);

[0492] Arg^(26,34)Lys³⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0493] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-37);

[0494] Arg²⁶Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0495] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0496] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0497] Gly⁸Lys²⁶(N^(ε)(ω-carboxynonadecanoyl))Arg³⁴-GLP-1(7-38);

[0498] Arg^(26,34)Lys³⁶(N^(ε)-(ω-carboxynonadecanoyl) ))-GLP-1(7-38);

[0499] Arg^(26,34)Lys³⁸(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0500] Gly⁸Arg²⁶Lys³⁸(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0501] Arg²⁶Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-39);

[0502] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-39);

[0503] Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl)Arg³⁴-GLP-1(7-39);

[0504] Gly⁸Lys²⁶(N^(ε)-((ω-carboxynonadecanoyl))Arg³⁴-GLP-1(7-39);

[0505] Arg^(26,34)Lys³⁶(N^(ε)-(ω-carboxynonadecanoyl ))-GLP-1(7-39);

[0506] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-carboxynonadecanoyl))-GLP-1(7-39);

[0507] Arg²⁶Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0508] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0509] Lys²⁶(N^(ε)(ω-carboxynonadecanoyl))Arg³⁴-GLP-1(7-40);

[0510] Gly⁸Lys²⁶(N^(ε)-(ω-carboxynonadecanoyl)))Arg³⁴-GLP-1(7-40);

[0511] Arg^(26,34)Lys³⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0512] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0513] Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0514] Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0515] Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0516] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0517] Gly⁸Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0518] Gly⁸Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0519] Arg²⁶Lys³⁴(N⁸-(7-deoxycholoyl))-GLP-1(7-37);

[0520] Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0521] Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0522] Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0523] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0524] Gly⁸Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0525] Gly⁸Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0526] Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0527] Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0528] Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0529] Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0530] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0531] Gly⁸Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0532] Gly⁸Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0533] Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0534] Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0535] Lys³⁴(N^(ε)-( 7-deoxycholoyl))-GLP-1(7-40);

[0536] Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0537] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0538] Gly⁸Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0539] Gly⁸Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0540] Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0541] Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36);

[0542] Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36);

[0543] Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36);

[0544] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36);

[0545] Gly⁸Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36);

[0546] Gly⁸Lys^(26,34) bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36);

[0547] Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36);

[0548] Lys²⁶ (N^(ε)-(7-deoxycholoyl))-GLP-1(7-35);

[0549] Lys³⁴ (N^(ε)-(7-deoxycholoyl))-GLP-1(7-35);

[0550] Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-35);

[0551] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-35);

[0552] Gly⁸Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-35);

[0553] Gly⁸Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-35);

[0554] Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-35);

[0555] Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0556] Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0557] Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0558] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0559] Gly⁸Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0560] Gly⁸Lys^(26,34)-bis(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0561] Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0562] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0563] Lys²⁶(N^(ε)-(7-deoxycholoyl))Arg³⁴-GLP-1(7-37);

[0564] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))Arg³⁴-GLP-1(7-37);

[0565] Arg^(26,34)Lys³⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0566] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0567] Lys²⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-37);

[0568] Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-37);

[0569] Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-37);

[0570] Gly⁸Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-37);

[0571] Gly⁸Lys³⁴ (N^(ε)-(choloyl))-GLP-1(7-37);

[0572] Gly⁸Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-37);

[0573] Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-37);

[0574] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0575] Lys²⁶(N^(ε)-(7-deoxycholoyl))Arg³⁴-GLP-1(7-38);

[0576] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))Arg³⁴-GLP-1(7-38);

[0577] Arg^(26,34)Lys³⁸(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0578] Arg^(26,34)Lys³⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-38);

[0579] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(7-deoxy choloyl))-GLP-1(7-38);

[0580] Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-38);

[0581] Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-38);

[0582] Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-38);

[0583] Gly⁸Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-38);

[0584] Gly⁸Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-38);

[0585] Gly⁸Lys^(26,34) bis(N^(ε)-(choloyl))-GLP-1(7-38);

[0586] Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-38);

[0587] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0588] Lys²⁶(N^(ε)-(7-deoxycholoyl))Arg³⁴-GLP-1(7-39);

[0589] Gly⁸Lys²⁶(N^(ε)-(7-deoxycholoyl))Arg³⁴-GLP-1(7-39);

[0590] Arg^(26,34)Lys³⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0591] Gly⁸Arg^(26,34)(N^(ε)-(7-deoxycholoyl))-GLP-1(7-39);

[0592] Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-39);

[0593] Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-39);

[0594] Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-39);

[0595] Gly⁸Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-39);

[0596] Gly⁸Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-39);

[0597] Gly⁸Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-39);

[0598] Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-₁(7-39);

[0599] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(deoxycholoyl))-GLP-1(7-40);

[0600] Lys²⁶(N^(ε)-(7-deoxycholoyl))Arg³⁴-GLP-1(7-40);

[0601] Gly⁸Lys²⁶(N^(ε)-(7deoxycholoyl))Arg³⁴-GLP-1(7-40);

[0602] Arg^(26,34)Lys³⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0603] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0604] Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-40);

[0605] Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-40);

[0606] Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-40);

[0607] Gly⁸Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-40);

[0608] Gly⁸Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-40);

[0609] Gly⁸Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-40);

[0610] Arg²⁶Lys³⁴(N^(ε)-(7-deoxycholoyl))-GLP-1(7-40);

[0611] Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-36);

[0612] Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-36);

[0613] Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-36);

[0614] Gly⁸Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-36);

[0615] Gly⁸Lys³⁴(N^(ε)-(choloyl))-GLP-₁(7-36);

[0616] Gly⁸Lys^(26,34)-bis(N^(ε)-(Choloyl))-GLP-1(7-36);

[0617] Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-36);

[0618] Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-35);

[0619] Lys³⁴ (N^(ε)-(choloyl))-GLP-1(7-35);

[0620] Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-35);

[0621] Gly⁸Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-35);

[0622] Gly⁸Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-35);

[0623] Gly⁸Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-35);

[0624] Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-35);

[0625] Lys²⁶(N^(ε)-(choloyl))-GLP-1(7-36)amide;

[0626] Lys³⁴(N³⁴(N^(ε)-(choloyl))-GLP-1(7-36)amide;

[0627] Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-36)amide;

[0628] Gly⁸Lys⁸(N^(ε)-(choloyl))-GLP-1(7-36)amide;

[0629] Gly⁸Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-36)amide;

[0630] Gly⁸Lys^(26,34)-bis(N^(ε)-(choloyl))-GLP-1(7-36)amide;

[0631] Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-36)amide;

[0632] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-37);

[0633] Lys²⁶(N^(ε)-(choloyl))Arg³⁴-GLP-1(7-37);

[0634] Gly⁸Lys²⁶(N^(ε)-(choloyl))Arg³⁴-GLP-1(7-37);

[0635] Arg^(26,34)Lys³⁶(N^(ε)-(choloyl))-GLP-1(7-36)amide;

[0636] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(choloyl))-GLP-1(7-37);

[0637] Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0638] Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0639] Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0640] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0641] Gly⁸Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0642] Gly⁸Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0643] Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0644] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-38);

[0645] Lys²⁶(N^(ε)-(choloyl))Arg³⁴-GLP-₁(7-38);

[0646] Gly⁸Lys²⁶(N^(ε)-(choloyl))Arg³⁴-GLP-1(7-38);

[0647] Arg^(26,34)Lys³⁶(N^(ε)-(choloyl))-GLP-1(7-38);

[0648] Arg^(26,34)Lys³⁸(N^(ε)-(choloyl))-GLP-1(7-38);

[0649] Gly⁸Arg Lys^(26,36)(N^(ε)-(choloyl))-GLP-1(7-38);

[0650] Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0651] Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0652] Lys^(26,34) -bis(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0653] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0654] Gly⁸Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0655] Gly⁸Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0656] Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0657] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-₁(7-39);

[0658] Lys²⁶(N^(ε)-(choloyl))Arg³⁴-GLP-1(7-39);

[0659] Gly⁸Lys²⁶(N^(ε)-(choloyl))Arg³⁴-GLP-1(7-39);

[0660] Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0661] Gly⁸Arg^(26,34)(N^(ε)-(choloyl))-GLP-1(7-39);

[0662] Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0663] Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0664] Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0665] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0666] Gly⁸Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0667] Gly⁸Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0668] Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-39 );

[0669] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(choloyl))-GLP-1(7-40);

[0670] Lys²⁶(N^(ε)-(choloyl))Arg³⁴-GLP-1(7-40);

[0671] Gly⁸Lys²⁶(N^(ε)-(choloyl))Arg³⁴-GLP-1(7-40);

[0672] Arg^(26,34)Lys³⁶(N^(ε)-(choloyl))-GLP-1(7-40);

[0673] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(choloyl))-GLP-1(7-40);

[0674] Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-40);

[0675] Lys34(N^(ε)-(lithocholoyl))-GLP-1(7-40);

[0676] Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-40);

[0677] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-40);

[0678] Gly⁸Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-40);

[0679] Gly⁸Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-40);

[0680] Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0681] Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-36);

[0682] Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-36);

[0683] Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-36);

[0684] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-36);

[0685] Gly⁸Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-36);

[0686] Gly⁸Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-36);

[0687] Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-36);

[0688] Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-35);

[0689] Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-35);

[0690] Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-35);

[0691] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-35);

[0692] Gly⁸Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-35);

[0693] Gly⁸Lys^(26,34)-bis(N-^(ε)-(lithocholoyl))-GLP-1(7-35);

[0694] Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-35);

[0695] Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-36)amide;

[0696] Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-36)amide;

[0697] Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-36)amide;

[0698] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))-GLP-1(7-36)amide;

[0699] Gly⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-36)amide;

[0700] Gly⁸Lys^(26,34)-bis(N^(ε)-(lithocholoyl))-GLP-1(7-36)amide;

[0701] Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-36)amide;

[0702] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP₁(7-37);

[0703] Lys²⁶(N^(ε)-(lithocholoyl))Arg³⁴GLP-₁(7-37);

[0704] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))Arg³⁴-GLP-1(7-37);

[0705] Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0706] Arg^(26,34)Lys³⁸(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0707] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-37);

[0708] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0709] Lys²⁶(N^(ε)-(lithocholoyl))Arg³⁴-GLP-1(7-38);

[0710] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))Arg³⁴-GLP-1(7-38);

[0711] Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0712] Arg^(26,34)Lys³⁸(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0713] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-38);

[0714] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0715] Lys²⁶ (N^(ε)-(lithocholoyl))Arg³⁴-GLP-1(7-39);

[0716] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))Arg³⁴-GLP-1(7-39);

[0717] Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0718] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-39);

[0719] Gly⁸Arg²⁶Lys³⁴(N^(ε)-(lithocholoyl))-GLP-1(7-40);

[0720] Lys²⁶(N^(ε)-(lithocholoyl))Arg³⁴-GLP-1(7-40);

[0721] Gly⁸Lys²⁶(N^(ε)-(lithocholoyl))Arg³⁴-GLP-1(7-40);

[0722] Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-40) and

[0723] Gly⁸Arg^(26,34)Lys³⁶(N^(ε)-(lithocholoyl))-GLP-1(7-40). Each oneof these specific GLP-1 derivatives constitutes an alternativeembodiment of the invention.

[0724] A more preferred GLP-1 derivative is Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37). Another morepreferred GLP-1 derivative is Arg²⁶,Lys³⁴(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37).

[0725] GLP-1 analogues and derivatives which can be used according tothe present invention includes those referred to in WO 99/43705 (NovoNordisk A/S), WO 99/43706 (Novo Nordisk A/S), WO 99/43707 (Novo NordiskA/S), WO 98/08871(Novo Nordisk A/S), WO 99/43708 (Novo Nordisk A/S), WO99/43341(Novo Nordisk A/S), WO 87/06941(The General HospitalCorporation), WO 90/11296 (The General Hospital Corporation), WO91/11457 (Buckley et al.), WO 98/43658 (Eli Lilly & Co.), EP 0708179-A2(Eli Lilly & Co.), EP 0699686-A2 (Eli Lilly & Co.) which are includedherein by reference.

[0726] However, protracted acting GLP-1 derivatives, in particular thosedescribed in WO 98/08871 are more preferred. The most preferred GLP-1derivatives are those in which the parent peptide has the formulaGLP-1(7-C), wherein C is 36, 37, 38, 39, 40, 41, 42, 43, 44 and 45,wherein optionally a total of up to fifteen, preferably up to ten aminoacid residues have been exchanged with any α-amino acid residue whichcan be coded for by the genetic code, said parent peptide comprising oneor two lipophilic substituents having 4 to 40 carbon atoms, preferablyfrom 8 to 25 carbon atoms, optionally via a spacer (such as γ-Glu orβ-Ala). The substituents are preferably selected from acyl groups ofstraight-chained or branched fatty acids.

[0727] GLP-1 analogues and derivatives that include an N-terminalimidazole group and optionally an unbranched C₆-C₁₀ acyl group attachedto the lysine residue in position 34 are also embodiments of theinvention.

[0728] In a still further embodiment of the invention the GLP-1 agonistis selected from exendin as well as analogs, derivatives, and fragmentsthereof, e.g. exendin-3 and -4.

[0729] Examples of exendin as well as analogs, derivatives, andfragments thereof to be included within the present invention are thosedisclosed in WO 9746584 and U.S. Pat. No. 5,424,286. U.S. Pat. No.5,424,286 describes a method for stimulating insulin release withexendin polypeptide(s). The exendin polypeptides disclosed includeHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGX; wherein X=P or Y, andHX1X2GTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; wherein X1X2=SD (exendin-3)or GE (exendin-4)). The exendin-3 and -4 and fragments are useful intreatment of diabetes mellitus (types I or II) and prevention ofhyperglycaemia. They normalise hyperglycaemia through glucose-dependent,insulin-independent and insulin-dependent mechanisms. Exendin-4 isspecific for exendin receptors, i.e. it does not interact withvasoactive intestinal peptide receptors. WO 9746584 describes truncatedversions of exendin peptide(s) for treating diabetes. The disclosedpeptides increase secretion and biosynthesis of insulin, but reducethose of glucagon. The truncated peptides can be made more economicallythan full length versions.

[0730] In a still further embodiment of the invention the GLP-1 agonistis a non-peptide.

[0731] In a further embodiment the GLP-1 agonist binds to a GLP-1receptor with an affinity constant, K_(D), below 1 μM, preferably below100 nM.

[0732] In a still further embodiment the GLP-1 agonist is a non-peptide,which binds to a GLP-1 receptor with an affinity constant, K_(D), below1 μM, preferably below 100 nM.

[0733] Any possible combination of two or more of the embodimentsdescribed herein, is comprised within the scope of the presentinvention. The term “GLP-1” is intended to mean GLP-1(7-37) orGLP-1(7-36) amide.

[0734] The term “treatment” is defined as the management and care of apatient for the purpose of combating the disease, condition, or disorderand includes the administration of a GLP-1 agonist to prevent the onsetof the symptoms or complications, or alleviating the symptoms orcomplications, or eliminating the disease, condition, or disorder.

[0735] In the present context “a GLP-1 agonist” is intended to indicatea molecule, preferably GLP-1 or an analogue or a derivative thereof, orexendin or an analogue or a derivative thereof, or a non-peptide, whichbinds to a GLP-1 receptor with an affinity constant, K_(D), below 1 μM,preferably below 100 nM. Methods for identifying GLP-1 agonists aredescribed in WO 93/19175 (Novo Nordisk A/S).

[0736] In the present context “a GLP-1 agonist” is also intended tocomprise active metabolites and prodrugs thereof, such as activemetabolites and prodrugs of GLP-1 or an analogue or a derivativethereof, or exendin or an analogue or a derivative thereof, or anon-peptide. A “metabolite” is an active derivative of a GLP-1 agonistproduced when the GLP-1 agonist is metabolized. A “prodrug” is acompound which is either metabolized to a GLP-1 agonist or ismetabolized to the same metabolite(s) as a GLP-1 agonist.

[0737] In the present text, the designation “an analogue” is used todesignate a peptide wherein one or more amino acid residues of theparent peptide have been substituted by another amino acid residueand/or wherein one or more amino acid residues of the parent peptidehave been deleted and/or wherein one or more amino acid residues havebeen added to the parent peptide. Such addition can take place either inthe peptide, at the N-terminal end or at the C-terminal end of theparent peptide, or any combination thereof.

[0738] The term “derivative” is used in the present text to designate apeptide in which one or more of the amino acid residues of the parentpeptide have been chemically modified, e.g. by alkylation, acylation,ester formation or amide formation.

[0739] The term “a GLP-1 derivative” is used in the present text todesignate a derivative of GLP-1 or an analogue thereof. In the presenttext, the parent peptide from which such a derivative is formallyderived is in some places referred to as the “GLP-1 moiety” of thederivative.

[0740] In the present specification “premature occlusive arterialdisease” is intended to comprise those disease-states, which arecharacterized by the closure of an artery or the progress of closing anartery, and which a) develop earlier in life than normal and b) areassociated with high levels of Lp(a) in the plasma; and includes, i.a.,stroke, coronary artery disease, atherosclerosis, arteriosclerosis,myocardial infarction, restenosis, peripheral artery disease and bypassgraft stenosis.

[0741] For a description of suitable dosage forms, dosage ranges,pharmaceutical formulations etc. reference is made to eg. WO 91/11457,WO 98/08871, WO 9746584, or U.S. Pat. No. 5,424,286.

[0742] The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral.

[0743] Pharmaceutical compositions (or medicaments) containing a GLP-1agonist, may be administered parenterally to patients in need of such atreatment. Parenteral administration may be performed by subcutaneous,intramuscular or intravenous injection by means of a syringe, optionallya pen-like syringe. Alternatively, parenteral administration can beperformed by means of an infusion pump. A further option is acomposition which may be a powder or a liquid for the administration ofthe GLP-1 agonist in the form of a nasal or pulmonal spray. As a stillfurther option, the GLP-1 agonist can also be administeredtransdermally, e.g. from a patch, optionally a iontophoretic patch, ortransmucosally, e.g. bucally. As a still further option, the GLP-1agonist (in particular GLP-1 or an analogue thereof) can also beadministered by gene therapy, such as by implanting a cell linetransformed with a vector such that it secretes the GLP-1 agonist. Theimplanted cells may be encapsulated in semi permeable membranes, e.g.macro- or microencapsulated. The above mentioned possible ways toadminister a GLP-1 agonist are not considered as limiting the scope ofthe invention.

[0744] Pharmaceutical compositions containing a GLP-1 agonist may beprepared by conventional techniques, e.g. as described in Remington'sPharmaceutical Sciences, 1985 or in Remington: The Science and Practiceof Pharmacy, 19^(th) edition, 1995.

[0745] Thus, the injectable compositions of the GLP-1 agonist can beprepared using the conventional techniques of the pharmaceuticalindustry which involves dissolving and mixing the ingredients asappropriate to give the desired end product.

[0746] According to one procedure, the GLP-1 agonist is dissolved in anamount of water which is somewhat less than the final volume of thecomposition to be prepared. An isotonic agent, a preservative and abuffer is added as required and the pH value of the solution isadjusted—if necessary—using an acid, e.g. hydrochloric acid, or a base,e.g. aqueous sodium hydroxide as needed. Finally, the volume of thesolution is adjusted with water to give the desired concentration of theingredients.

[0747] Examples of isotonic agents are sodium chloride, mannitol andglycerol.

[0748] Examples of preservatives are phenol, m-cresol, methylp-hydroxybenzoate and benzyl alcohol.

[0749] Examples of suitable buffers are sodium acetate and sodiumphosphate.

[0750] Further to the above-mentioned components, solutions containing aGLP-1 agonist may also contain a surfactant in order to improve thesolubility and/or the stability of the GLP-1 agonist.

[0751] A composition for nasal administration of certain peptides may,for example, be prepared as described in European Patent No. 272097 (toNovo Nordisk ANS) or in WO 93/18785.

[0752] According to one embodiment of the present invention, the GLP-1agonist is provided in the form of a composition suitable foradministration by injection. Such a composition can either be aninjectable solution ready for use or it can be an amount of a solidcomposition, e.g. a lyophilised product, which has to be dissolved in asolvent before it can be injected. The injectable solution preferablycontains not less than about 2 mg/ml, preferably not less than about 5mg/ml, more preferred not less than about 10 mg/ml of the GLP-1 agonistand, preferably, not more than about 100 mg/ml of the GLP-1 agonist.

[0753] The GLP-1 agonist can be used in the treatment of variousdiseases. The particular GLP-1 agonist to be used and the optimal doselevel for any patient (effective amount) will depend on the disease tobe treated and on a variety of factors including the efficacy of thespecific peptide derivative employed, the age, body weight, physicalactivity, and diet of the patient, on a possible combination with otherdrugs, and on the severity of the case. It is recommended that thedosage of the GLP-1 agonist be determined for each individual patient bythose skilled in the art.

Experimental EXAMPLE 1

[0754] Acute and subchronic anorectic effects of Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37) (hereinafter GLP-1)were studied in both normal Wistar rats and a model of hypothalamicobesity (Wistar rats subjected to neonatal monosodium glutamatetreatment (MSG)). MSG lesioned rats were randomly assigned to groupsreceiving GLP-1 or vehicle. 100 μg/kg GLP-1 was administered bysubcutaneous injection twice daily. GLP-1 was dissolved in sterilephosphate buffered saline (50 mM, pH 7.4) to a final concentration ofeither 0.1 or 1 mg/ml. Solutions were always made fresh approximately 1hour prior to use and stored at 4° C. in sterile tubes. An inhibition offood intake was observed, accompanied by reduced body weight. Initialdecreases in water intake and increases in diuresis were normalisedwithin few days of treatment, and plasma parameters of renal functionremained normal throughout the experiment. Lowered plasma levels oftriglycerides were observed. In normal rats from 1.58±0.1 to 1.21±0.3 mMand in MSG rats from 2.27±0.3 to 1.49±0.1 mM.

EXAMPLE 2

[0755] The male Zucker Diabetic Fatty fa/fa (ZDF) rat is a model of Type2 diabetes. The rats are insulin resistant but normoglycemic from birthand they develop diabetes from about week 7 to week 10 of age. Duringthe transitional period, the animals go through a state of impairedglucose tolerance. Although the animals are hyperinsulinemic beforediabetes onset and during the early stages of diabetes, they later loseglucose-stimulated insulin secretion and finally become almostcompletely insulinopenic.

[0756] We have studied the effects of GLP-1 therapy during a period oftime when the animals would normally progress from having impairedglucose tolerance to having overt Type 2 diabetes. Three groups of maleZDF rats (Genetic Models Inc, Indianapolis, Ind., USA) were studied anddosed subcutaneously bi-daily with either vehicle (group A), 30 (groupB) or 150 μg/kg (group C) of GLP-1, n=6 per group. Animals were between7 and 8 weeks old when dosing was initiated, and fed glucose levels werenot different between the groups before dosing began. However, they wereelevated compared to a group of non-diabetic Sprague-Dawley rats who hadfed glucose levels significantly below the ZDF animals (6.4±0.6 vs5.8±0.8, mean±SD, p<0.02). This demonstrates the relative impairedglucose tolerant state of the ZDF animals when the study began. After 10days of dosing, group C had blood glucose levels during a normal 24-hourfeeding schedule that were unchanged compared to the initialmeasurements and they were significantly lower than the vehicle- andlow-dose-treated animals who were hyperglycemic. After 36 days ofdosing, an oral glucose tolerance test was performed in the animalsafter an 11-hour fast. One g/kg of glucose was administered by oralgavage and subsequent measurements of blood glucose and plasma insulinwere made. Also in this test, the glycemic level was significantly lowerin group C compared to groups A and B. These results demonstrate thattreatment with GLP-1 can prevent or delay the progression of impairedglucose tolerance to Type 2 diabetes.

[0757] In addition to the effects on blood glucose and insulin, we alsostudied the effects of long-term treatment on lipid parameters. Thus, atthe termination of the study, non-fasted plasma measurements of totalcholesterol, free fatty acids were performed. The results, summarized inTable 1, demonstrated a significant reduction in free fatty acids andtotal cholesterol in group C compared to group A. This demonstrates thattreatment with GLP-1 has lipid-lowering properties. TABLE 1 Lipidparameters. Data are expressed as mean ± SEM Free fatty Total acids (mM)cholesterol (mM) Group A 0.34 ± 0.01 2.8 ± 0.1 Group B 0.29 ± 0.04 2.9 ±0.1 Group C 0.20 ± 0.02 2.2 ± 0.1

[0758]

1 1 1 39 PRT Artificial Sequence Synthetic 1 His Xaa Xaa Gly Xaa Phe ThrXaa Asp Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa PheIle Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30 Xaa Xaa Xaa Xaa Xaa XaaXaa 35

1. Use of a GLP-1 agonist for the manufacture of a medicament forlowering total serum lipids.
 2. Use of a GLP-1 agonist for themanufacture of a medicament for lowering LDL.
 3. Use of a GLP-1 agonistfor the manufacture of a medicament for lowering smal, dense LDL
 4. Useof a GLP-1 agonist for the manufacture of a medicament for loweringVLDL.
 5. Use of a GLP-1 agonist for the manufacture of a medicament forlowering triglycerides.
 6. Use of a GLP-1 agonist for the manufacture ofa medicament for lowering cholesterol.
 7. Use of a GLP-1 agonist for themanufacture of a medicament for increasing HDL.
 8. Use of a GLP-1agonist for the manufacture of a medicament for lowering plasma levelsof Lp(a) in a human.
 9. Use of a GLP-1 agonist for the manufacture of amedicament for inhibiting generation of apo(a) in a human.
 10. Use of aGLP-1 agonist for the manufacture of a medicament for treatingdyslipidemia.
 11. The use according to any one of claims 1-10 whereinthe GLP-1 agonist binds to a GLP-1 receptor with an affinity constant,K_(D), below 1 μM.
 12. The use according to any one of claims 1-11wherein the GLP-1 agonist is selected from Arg²⁶,Lys³⁴(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37), Arg³⁴,Lys²⁶(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37), exendin-3, exendin-4,Val⁸-GLP-1(7-37), Thr⁸-GLP-1(7-37), Met⁸-GLP-1(7-37), Gly⁸-GLP-1(7-37).13. A method of lowering total serum lipids, which method comprisesadministering to a subject an effective amount of a GLP-1 agonist.
 14. Amethod of lowering LDL, which method comprises administering to asubject an effective amount of a GLP-1 agonist.
 15. A method of loweringsmall, dense LDL, which method comprises administering to a subject aneffective amount of a GLP-1 agonist
 16. A method of lowering VLDL, whichmethod comprises administering to a subject an effective amount of aGLP-1 agonist.
 17. A method of lowering triglycerides, which methodcomprises administering to a subject an effective amount of a GLP-1agonist.
 18. A method of lowering cholesterol, which method comprisesadministering to a subject an effective amount of a GLP-1 agonist.
 19. Amethod of increasing HDL, which method comprises administering to asubject an effective amount of a GLP-1 agonist.
 20. A method ofinhibiting generation of apo(a) in vitro or in vivo by administering aGLP-1 agonist.
 21. A method of lowering plasma levels of Lp(a) in ahuman, comprising administering to said human an effective amount of aGLP-1 agonist.
 22. A method of inhibiting generation of apo(a) in ahuman, comprising administering to said human an effective amount of aGLP-1 agonist.
 23. A method for treating dyslipideamia which methodcomprises administering to a subject an effective amount of a GLP-1agonist.
 24. The method according to any one of claims 13-23 wherein theGLP-1 agonist binds to a GLP-1 receptor with an affinity constant,K_(D), below 1 μM.
 25. The method according to any one of claims 13-23wherein the GLP-1 agonist is selected from Arg²⁶,Lys³⁴(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37), Arg³⁴,Lys²⁶(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37), exendin-3, exendin-4,Val⁸-GLP-1(7-37), Thr⁸-GLP-1(7-37), Met⁸-GLP-1(7-37), Gly⁸-GLP-1(7-37).